Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Enteroviruses cause various acute and chronic diseases. The most promising therapeutics for these infections are capsid-binding molecules. These can act against a broad spectrum of enteroviruses, but emerging resistant virus variants threaten their efficacy. All known enterovirus variants with high-level resistance toward capsid-binding molecules have mutations of residues directly involved in the formation of the hydrophobic binding site. This is a first report of substitutions outside the binding pocket causing this type of drug resistance: I1207K and I1207R of the viral capsid protein 1 of coxsackievirus B3. Both substitutions completely abolish the antiviral activity of pleconaril (a capsid-binding molecule) but do not affect viral replication rates in vitro. Molecular dynamics simulations indicate that the resistance mechanism is mediated by a conformational rearrangement of R1095, which is a neighboring residue of 1207 located at the heel of the binding pocket. These in
Date Issued
2015-09-25
Date Acceptance
2015-09-15
Citation
Antiviral Research, 2015, 123, pp.138-145
ISSN
1872-9096
Publisher
Elsevier
Start Page
138
End Page
145
Journal / Book Title
Antiviral Research
Volume
123
Copyright Statement
© 2015 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Subjects
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Virology
Antiviral
Enterovirus
Rhinovirus
Pleconaril
Drug susceptibility testing
Computational studies
HUMAN RHINOVIRUS SEROTYPES
3.5 ANGSTROM RESOLUTION
COXSACKIEVIRUS B3
ANTIVIRAL ACTIVITY
PLECONARIL
REPLICATION
INHIBITORS
MUTANTS
SUSCEPTIBILITY
NEURAMINIDASE
1108 Medical Microbiology
1115 Pharmacology And Pharmaceutical Sciences
Publication Status
Published